Society is concerned as to whether a threshold exists for adverse psychological and neurophysiological effects accompanying childhood low level lead (Pb) exposure. Many uncertainties remain concerning Pb (at low levels of exposure) as an etiological agent for various neuropsychological dysfunctions. The proposed animal studies address this question at the cellular and neurochemical level. Based on recent behavioral and neurochemical observations in Pb treated animals in this laboratory, as well as the consistent reports of a Pb-calcium (Ca) interaction in peripheral tissue preparations, the proposed studies are oriented towards delineating a common mechanism underlying CNS neurotransmitter insult following neonatal exposure to Pb. The hypothesis to be tested is: An inhibition by Pb of the flux of Ca across the nerve terminal membrane during neonatal CNS development will result in a persistent alteration in intraneuronal Ca regulation that will be reflected in a generalized alteration in transmitter release. To test this hypothesis the release of three representative neurotransmitters (using rapid superfusion), the influx of Ca (both fast and slow phases), and the efflux of Ca (using rapid superfusion) will be examined in "purified" synaptosomes obtained from various regions of the rat brain. The influence of Pb on these processes will be examined following both in vitro Pb exposure and in vivo (neonatal) Pb exposure. The in vivo Pb exposure studies will utilize an animal model analogous to asymptomatic Pb exposure in children. The indices of Pb body burden (ZPP, Blood Pb, regional brain Pb) will be closely monitored. Testing will be carried out at ages when brain Pb concentrations following neonatal Pb exposure are raised (day 30) and at later times when brain Pb concentrations approach control levels (day 90). The importance of the proposed research is that it will establish whether a generalized and persistent alteration in the neuronal Ca regulatory process, which controls a number of important cellular processes including neurotransmitter release, is the basis of CNS insult following neonatal Pb exposure.